The present invention relates to new cycloheptene compounds, to a process for their preparation and to pharmaceutical compositions containing them.
The compounds of the invention are useful as farnesyl transferase inhibitors.
A large number of proteins are subject to post-translational changes which alter their localisation and their function. In particular, lipid-type modifications allow certain proteins that are inactive in their free form to be anchored in the plasma membrane, which is a crucial step for ensuring their function. This applies to prenylation (Curr. Opin. Cell. Biol., 4, 1992, 1008-1016), which is catalysed by several enzymes: farnesyl transferase (FTase) and the two geranylgeranyl transferases (GGTase-I and GGTase-II) which couple a prenyl group to 15 (trans,trans-farnesyl) or 20 (all-trans-geranylgeranyl) carbons on the carboxy terminal moiety of substrate proteins (J. Biol. Chem., 271, 1996, 5289-5292; Curr. Opin. Struct. Biol., 7, 1997, 873-880). FTase catalyses that transfer, starting from farnesyl pyrophosphate, to form a thio ether bond on the cysteine of the terminal tetrapeptide consensus sequence CA1A2X found on substrate proteins, C denoting cysteine, A1 and A2 denoting an aliphatic amino acid and X denoting a serine, an alanine or a methionine. GGTase-I uses geranylgeranyl pyrophosphate as donor substrate for effecting a similar transfer, but this time the consensus sequence CAAX is terminated by a leucine or a phenylalanine. Those two heterodimeric enzymes share an alpha subunit of 48 kDa, and possess two distinct beta chains, although they have 30% homology of amino acid sequences. GGTase-II acts on terminal sequences of the XXCC and XCXC types and has alpha and beta subunits different from those of the afore-mentioned enzymes.
The interest in inhibiting one of those enzymes, FTase, is based on the implication in tumour progression of the prenylated oncogene Ras (Annu. Rev. Biochem., 56, 1987, 779-827). Ras proteins exist in four major forms, Harvey or H-Ras, N-Ras, and Kirsten or K-Ras A and B. Those proteins are expressed in a mutated form in at least a quarter of cancers with an even greater incidence for some histological types of tumour and according to the form of Ras. For example, mutations of K-Ras B are found in 80 to 90% of pancreatic carcinomas and 30 to 60% of colon cancers (Int. J. Oncol., 7, 1995, 413-421). Numerous preclinical data have demonstrated the role of that oncogene in tumour progression, more especially in cell growth phenomena. It is an essential link in the transmission of extracellular signalsxe2x80x94such as those activated by growth factorsxe2x80x94to diverse cytosolic kinases and then to the nucleus, for integration in terms of proliferation, cell death and cell survival (Cancer Met. Rev., 13, 1994, 67-89; Curr. Opin. Genetics and Develop., 8, 1998, 49-54; J. Biol. Chem. 273, 1998, 19925-19928), or of regulation with the tumour environmentxe2x80x94angiogenesis in particular (Cancer Res., 55, 1995, 4575-4580).
The search for FTase inhibitors is thus of considerable interest in oncology (Curr. Opin. Chem. Biol., 2, 1998, 40-48). As 0.5% of animal proteins are probably prenylated and in the majority geranylgeranylated, specific inhibitors of FTase relative to the GGTases, and more especially GGTase-I, which is similar in structure to FTase, are of considerable interest. The first work with such inhibitors, peptidomimetic analogues of the farnesylation consensus sequence, and the following work with molecules obtained by chemical library screening, confirmed the anti-tumour strategy in in vitro and animal experiments (Annu. Rev. Pharmacol. Toxicol., 37, 1997, 143-166; Biochim. Biophys. Acta, 1423, 1999, C19-C30; Cancer Res., 58, 1998, 4947-4956). Fibroblasts specially transfected with the mutated H-Ras protein gene and implanted in an animal develop a tumour mass the growth of which is reduced as a function of the dose of FTase inhibitor received by the animal. In the case of transgenic animals that express a mutated form of H-Ras under the control of an appropriate promoter causing the random appearance of spontaneous mammary or salivary tumours, those same inhibitors bring about the regression of established tumours and block the appearance of new ones for the duration of the treatment. Finally, such products are also active in reducing the growth of human xenotransplants in the mouse, with a possible effect of increasing survival, depending on the model. The mutated Ras protein is not the only indirect target of those inhibitors in tumour pathology. The study of multiple tumour models has enabled confirmation of inhibition of tumour growth independently of the presence of mutated Ras proteins. That effect could be partly associated with a direct antiangiogenic activity and thus could be independent of the oncogenic profile of the tumour (Eur. J. Cancer, 35, 1999, 1394-1401). This observation reinforces and increases the potential for anti-tumour use of that class of inhibitors, and the absence of debilitating side effects on normal cell functions is also favourable for the inhibition of FTase in any pathology associated with mechanisms changed or amplified by a farnesylated protein or by farnesylated proteins. Aside from cancer, this applies especially, for example, to restenosis following angioplasty or vascular surgery, and to type I neurofibromatosis (Mol. Cell. Biol., 17, 1997, 862-872).
The compounds of the invention have a novel structure and are capable of selective inhibition of FTase relative to the GGTases. They will accordingly be useful in the treatment of all pathologies associated with intracellular signalling through Ras proteins or other farnesylated proteins, and in pathologies associated with angiogenesis amplification. They will thus be of use in the treatment of cancer, but also in the treatment of restenosis following angioplasty or vascular surgery, and in the treatment of type I neurofibromatosis.
The present invention relates to compounds of formula (I): 
wherein:
X represents a bond or a group selected from alkylene, CO, S(O)n, *xe2x80x94S(O)nxe2x80x94A1xe2x80x94, *xe2x80x94COxe2x80x94A1xe2x80x94, xe2x80x94A1xe2x80x94S(O)nxe2x80x94Axe2x80x21xe2x80x94 and xe2x80x94A1xe2x80x94COxe2x80x94Axe2x80x21xe2x80x94 (wherein A1 and Axe2x80x21, identical or different, represent an alkylene group and n is 0, 1 or 2), the symbol xe2x80x9c*xe2x80x9d indicating the point of attachment of those groups to the cycloheptene,
Y represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, each of those groups being unsubstituted or substituted by one or more, identical or different, R8 groups,
R1, R2, R3 and R4 each independently of the others represent a hydrogen atom or an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, each of those groups being unsubstituted or substituted by one or more, identical or different, R8 groups,
or R1, R2, R3 and R4, taken in pairs, together form a bond,
or R1 and R2, or R2 and R3, or R3 and R4, taken in pairs with the carbon atoms to which they are bonded, form a fused benzene ring or a fused aromatic or partially unsaturated heterocycle, having 5 or 6 ring members and containing 1 or 2 hetero atoms selected from nitrogen, oxygen and sulphur, on the understanding that only one ring can be fused on the 7-membered structure,
T represents a xe2x80x94CH(R5)xe2x80x94, xe2x80x94N(R5)xe2x80x94 or *xe2x80x94N(R5)COxe2x80x94 group (wherein R5 represents a hydrogen atom or an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group, each of those groups being unsubstituted or substituted by one or more, identical or different, R7 groups), the symbol xe2x80x9c*xe2x80x9d indicating the point of attachment of the group to the cycloheptene,
V represents a hydrogen atom or an aryl or heteroaryl group, each of those groups being unsubstituted or substituted by one or more, identical or different, R7 groups,
A2 represents a [C(R6)(Rxe2x80x26)]p group wherein p is 0, 1, 2, 3 or 4 when T represents a xe2x80x94CH(R5)xe2x80x94 or *xe2x80x94N(R5)COxe2x80x94 group, or p is 1, 2, 3 or 4 when T represents an xe2x80x94N(R5)xe2x80x94 group; and R6 and Rxe2x80x26, which may be identical or different, represent a hydrogen atom or an alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkylalkyl group, an R9 group or an alkyl group substituted by an R9 group (wherein R9 represents an xe2x80x94OR5, xe2x80x94N(R5)(Rxe2x80x25), xe2x80x94S(O)mR5, xe2x80x94CON(R5)(Rxe2x80x25), xe2x80x94N(R5)CORxe2x80x25, xe2x80x94N(R5)SO2Rxe2x80x25, xe2x80x94SO2N(R5)(Rxe2x80x25) or xe2x80x94N(R5)COO(Rxe2x80x25) group, m being 0, 1 or 2, and Rxe2x80x25 can have any of the meanings of R5),
R7 represents a halogen atom or an alkyl, alkoxy, hydroxy, mercapto, alkylthio, cyano, amino (optionally substituted by one or two alkyl groups), nitro, carboxy, alkoxycarbonyl, aminocarbonyl (optionally substituted by one or two alkyl groups), carbamoyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocycloalkyl or unsubstituted or substituted heterocycloalkylalkyl group,
R8 represents a halogen atom, or an oxo, hydroxy, cyano, nitro, carboxy, alkoxycarbonyl or perhaloalkyl group or a xe2x80x94Uxe2x80x94R80 or xe2x80x94A80xe2x80x94Uxe2x80x94R80 group (wherein A80 represents an alkylene group; U represents a bond, an oxygen atom or a group selected from NH, S(O)m, NHCO, CONH, SO2NH and NHSO2, m being 0, 1 or 2; and R80 is a group selected from alkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl),
it being understood that:
the term xe2x80x9calkylxe2x80x9d denotes a linear or branched group containing from 1 to 6 carbon atoms,
the term xe2x80x9calkylenexe2x80x9d denotes a linear or branched bivalent group containing from 1 to 6 carbon atoms,
the term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated cyclic group containing from 3 to 8 carbon atoms,
the term xe2x80x9cheterocycloalkylxe2x80x9d denotes a saturated or partially unsaturated cyclic group having from 5 to 7 ring members and containing from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur,
the term xe2x80x9carylxe2x80x9d denotes a phenyl or naphthyl group,
the term xe2x80x9cheteroarylxe2x80x9d denotes a mono- or bi-cyclic group that is aromatic or contains at least one aromatic ring, has from 5 to 11 ring members and contains from 1 to 5 hetero atoms selected from nitrogen, oxygen and sulphur,
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms xe2x80x9carylxe2x80x9d, xe2x80x9cheteroarylxe2x80x9d, xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9cheterocycloalkylxe2x80x9d means that those groups may be substituted by one or more identical or different groups selected from cyano, alkylcarbonyl, aminocarbonyl (optionally substituted by one or two alkyl groups) and halogen atoms,
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms xe2x80x9carylalkylxe2x80x9d, xe2x80x9cheteroarylalkylxe2x80x9d, xe2x80x9ccycloalkylalkylxe2x80x9d and xe2x80x9cheterocycloalkylalkylxe2x80x9d means that the cyclic moiety of those groups may be substituted by one or more identical or different groups selected from oxo, cyano, alkylcarbonyl, aminocarbonyl (optionally substituted by one or two alkyl groups) and halogen atoms,
their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
In the compounds of formula (I), X preferably represents a bond.
Preferred compounds of formula (I) are those wherein Y represents an aryl group (preferably phenyl optionally substituted by R8).
An advantageous aspect of the invention relates to compounds of formula (I) wherein each of R1, R2, R3 and R4 represents a hydrogen atom.
More especially, the invention relates to compounds of formula (I) wherein T represents an xe2x80x94N(R5)xe2x80x94 group and, more especially still, an xe2x80x94NHxe2x80x94 group.
Preferred A2 groups are the groups methylene, ethylene, (4-cyanophenyl)methylene, (4-chlorophenyl)methylene, (4-cyanobenzyl)methylene and (4-chlorobenzyl)methylene.
Very advantageously, V represents a heteroaryl group, such as, for example, the groups pyridyl and 1H-imidazolyl, those groups preferably being substituted by an optionally substituted arylalkyl group, such as, for example, the group p-cyanobenzyl or p-chlorobenzyl.
The preferred Vxe2x80x94A2xe2x80x94Txe2x80x94 group of the invention is the group [(4-cyanobenzyl)-1H-imidazol-5-yl]methylamino.
In the preferred compounds of formula (I) when V is substituted by R7, R7 represents an optionally substituted arylalkyl or optionally substituted heteroarylalkyl group. Those groups are advantageously substituted by a halogen atom or by a cyano group. An especially advantageous aspect of the invention relates to compounds of formula (I) wherein X represents a bond, Y represents an aryl group optionally substituted by R8, each of R1, R2, R3 and R4 represents a hydrogen atom, T represents an xe2x80x94N(R5)xe2x80x94 group and more especially still an xe2x80x94NHxe2x80x94 group, A2 represents a xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, (4-cyanophenyl)methylene, (4-chlorophenyl)methylene, (4-cyanobenzyl)methylene or (4-chlorobenzyl)methylene group and V represents a heteroaryl group, such as, for example, the groups pyridyl and 1H-imidazolyl optionally substituted by R7.
Among the preferred compounds of formula (I), there may be mentioned more especially: 4-{[5-({[3-(2-methylphenyl)-2-cyclohepten-1-yl]amino}methyl)-1H-imidazol-1-yl]-methyl}benzonitrile, 4-{[5-({[3-(3-methylphenyl)-2-cyclohepten-1-yl]amino}methyl)-1H-imidazol-1-yl]methyl}benzonitrile and 4-{[5-({[3-(3-chlorophenyl)-2-cyclohepten-1-yl]amino}methyl)-1H-imidazol-1-yl]methyl}benzonitrile.
The present invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): 
wherein R1, R2, R3 and R4 are as defined for formula (I),
the carbonyl function of which reacts with an organometallic compound of formula Lixe2x80x94Xxe2x80x94Y wherein X and Y are as defined for formula (I), to yield a compound of formula (III): 
wherein R1, R2, R3, R4, X and Y are as defined hereinbefore,
which is subjected to an isomerisation reaction in an acidic medium, to yield a compound of formula (IV): 
wherein R1, R2, R3, R4, X and Y are as defined hereinbefore,
which compound of formula (IV), after conversion of the hydroxyl function to a leaving group, is subjected to:
the introduction of a reactive function by the action of a silyl compound, such as Me3SiCN, CH2xe2x95x90CHxe2x80x94CH2xe2x80x94SiMe3 or CH2xe2x95x90C(Oalk)(OSiMe3) wherein alk represents an alkyl group, and then to condensation of the appropriate groups to yield a compound of formula (I/a) 
xe2x80x83a particular case of the compounds of formula (I) wherein R1, R2, R3, R4, R5, A2, V, X and Y are as defined hereinbefore,
or the action of sodium azide, to yield, after hydrolysis in the presence of triphenylphosphine, an amine of formula (V): 
xe2x80x83wherein R1, R2, R3, R4, X and Y are as defined hereinbefore,
which compound of formula (V) is condensed with an aldehyde of formula: 
wherein V is as defined hereinbefore, R6 and Rxe2x80x26 are as defined for formula (I), Rxe2x80x36 represents the same atoms or groups as those defined for R6 or Rxe2x80x26, and p is 1, 2, 3 or 4, to yield a compound of formula (I/b): 
a particular case of the compounds of formula (I) wherein R1, R2, R3, R4, R6, Rxe2x80x26, Rxe2x80x36, V, X, Y and p are as defined hereinbefore,
[certain compounds of formula (I/b) may also be obtained starting from the compound of formula (IIxe2x80x2): 
xe2x80x83wherein R1, R2, R3 and R4 are as defined hereinbefore,
which, after the formation of the corresponding silyl ether, is subjected to the action, in a strong basic medium, of a compound Yxe2x80x94Xxe2x80x2xe2x80x94CHO wherein Y is as defined hereinbefore and Xxe2x80x2 represents a bond or an alkylene group, to yield, after deprotection, a compound of formula (IIIxe2x80x2): 
xe2x80x83wherein R1, R2, R3, R4, Xxe2x80x2 and Y are as defined hereinbefore,
which is condensed with an amine of formula Vxe2x80x94A2xe2x80x94NH2 wherein V and A2 are as defined hereinbefore, to obtain a compound of formula (I/ba), a particular case of the compounds of formula (I/b): 
xe2x80x83wherein R1, R2, R3, R4, V, A2, Xxe2x80x2 and Y are as defined hereinbefore],
or which compound of formula (V) is subjected to an acylation reaction with a compound of formula Vxe2x80x94A2xe2x80x94CO-Hal wherein V and A2 are as defined for formula (I) and Hal represents a halogen atom, or to coupling with a carboxylic acid of formula Vxe2x80x94A2-COOH wherein V and A2 are as defined for formula (I), to yield a compound of formula (Ixe2x80x2/b): 
wherein R1, R2, R3, R4, A2, V, X and Y are as defined hereinbefore,
which compounds (I/b) and (Ixe2x80x2/b) may be subjected to the same type of condensation as before, with an aldehyde of formula Rxe2x80x35CHO, or with an acyl halide of formula Rxe2x80x35xe2x80x94CO-Hal, or with a carboxylic acid of formula Rxe2x80x35xe2x80x94COOH, wherein Rxe2x80x35 can have any of the meanings of R5 with the exception of a hydrogen atom, to yield a compound of formula (I/c): 
a particular case of the compounds of formula (I) wherein R1, R2, R3, R4, R5, A2, V, X and Y are as defined hereinbefore,
which compounds of formulae (I/a), (I/b), (Ixe2x80x2/b) and (I/c) constitute the totality of the compounds of formula (I),
which may, if necessary, be purified according to a conventional purification technique,
are separated, where appropriate, into their isomers according to a conventional separation technique,
which are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral, nasal or transdermal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, etc.
The useful dosage varies according to the age and weight of the patient, the nature and severity of the disorder and the route of administration, which may be oral, nasal, rectal or parenteral. Generally, the unit dose ranges from 0.05 to 500 mg per 24 hours for a treatment in from 1 to 3 administrations.
The following Examples illustrate the invention but do not limit it in any way. The structures of the compounds described were confirmed by the usual spectroscopic techniques.
The starting materials used are known products or are prepared according to known procedures.
Dihydroxyacetone in dimeric form (23.35 g/0.129 mol) and potassium thioisocyanate (25.18 g/0.259 mol) are added in succession to a solution of 25 g (0.233 mol) of 4-(aminomethyl)benzonitrile in 100 ml of isopropanol, and then the mixture is placed in an ice bath and 20 ml of acetic acid are added dropwise. The reaction mixture is stirred at room temperature for 48 hours. A precipitate is obtained, which is filtered off, washed with 50 ml of isopropanol and then twice with 50 ml of H2O, and subsequently dried. Thus crystals are obtained, which are used directly in the following desulphurisation step: 13 g (0.059 mol) of the previously obtained crystals are placed in 140 ml of a dilute solution of 10% nitric acid in water. At 0xc2x0 C., 0.1 g of sodium nitrite is added very slowly. Marked evolution of a brown gas is observed, and the mixture gradually becomes homogeneous. The reaction mixture is then stirred at room temperature for 3 hours and then filtered and extracted once with AcOEt. The aqueous phase is then rendered basic with a 5N sodium hydroxide solution, and subsequently extracted twice with AcOEt. The organic phase is washed with a saturated NaCl solution, and then dried over MgSO4. Evaporation in vacuo yields the title product.
Triethylamine (13.8 ml/99.6 mmol) and then SO3-pyridine complex (9.89 g/62.25 mmol) are added in succession to a solution of 4.6 g (24.9 mmol) of the compound obtained in Step A in 120 ml of DMSO, and the reaction mixture is stirred at room temperature for 30 minutes. The whole is then brought to 0xc2x0 C., hydrolysed with H2O, and then extracted several times with AcOEt. The organic phases are combined, washed with a saturated NaCl solution, dried over MgSO4, and evaporated to dryness to yield the title product.
3.83 g (49.7 mmol) of ammonium acetate and NaBH3CN (0.313 g/4.97 mmol) are added to a solution of the compound obtained in Preparation 1 (1.05 g/4.97 mmol) in 50 ml of methanol, and the whole is stirred at room temperature for 48 hours. The reaction mixture is then hydrolysed with a saturated NaHCO3 solution, and extracted with AcOEt. The organic extracts are then combined, dried over MgSO4 and concentrated to dryness. The residual oil is then purified over a column of silica gel (CH2Cl2, MeOH, NH4OH, 98/1.5/0.5) to yield the title product in the form of a white foam.
Preparations 3 to 13 are obtained according to the same process as in Preparations 1 and 2, replacing 4-(aminomethyl)benzonitrile by the appropriate substrate:
A solution of 4-bromobenzonitrile in solution in 20 ml of THF is added dropwise to a suspension of 1.44 g (0.022 mol) of zinc in 20 ml of anhydrous THF that has been brought to xe2x88x9220xc2x0 C. The whole is stirred at room temperature for 4 hours.
In parallel, 3-pyridinecarboxaldehyde (1.9 ml/0.02 mol) is brought to solution in 20 ml of anhydrous THF and then, at 0xc2x0 C., phenyl chloroformate (2.5 ml/0.02 mol) in solution in 10 ml of THF is added, and the reaction mixture is stirred at that temperature for 1 hour. A whitish precipitate is seen to form.
The previously obtained bromo-zinc compound is then transferred into the protected pyridine, and the whole is stirred at 0xc2x0 C. for 1.5 hours, and subsequently allowed to return gradually to room temperature and stirred for 1.5 hours at that temperature. Hydrolysis is carried out using a saturated NH4Cl solution, extraction is carried out with AcOEt, and the extract is washed with a saturated NaCl solution, followed by drying over MgSO4 and then evaporation to dryness. A brown oil is obtained, which is purified by chromatography over silica gel (heptane, 10% AcOEt) to obtain the title product.
The product obtained in Step A (2 g/0.0058 mol) is brought to solution in 80 ml of Decalin, and then 0.336 g (0.010 mol) of sulphur is added, and the whole is heated at 140-150xc2x0 C. for 24 hours. The reaction mixture is filtered and then concentrated. A brown oil is obtained, which is purified by chromatography over silica gel (heptane, 10% AcOEt 10%) to yield the title product.
Elemental Microanalysis
This compound is prepared according to the protocol described by D. J. Chadwick and R. I. Ngochindo, J. Chem. Soc., Perkin Trans., 481, 1984, starting from 10.2 g (0.15 mol) of imidazole, 20 g of a translucent yellow oil are obtained, which crystallises gradually at room temperature in the form of an amorphous solid in a yield of 93%. IR 1177 and 1391 cmxe2x88x921, xcexd (NSO2). NMR (CDCl3): 7.35, d, (1H); 7.25 d, (1H); 7.15 s, (1H); 2.31 s, (6H).
Elemental Microanalysis
This compound is prepared according to the protocol described by J. W. Kim, S. M. Abdelaal and L. Bauer J. Heterocyclic Chem., 611 1995, by lithiation of the compound obtained in Step B with n-butyllithium (1.6M solution in hexane) at xe2x88x9278xc2x0 C., followed by the addition of TBDMSiCl. After chromatography over silica gel (ethyl acetate in heptane), 2-[tert-butyl(dimethyl)silyl]-N,N-dimethyl-1H-imidazole-1-sulphonamide is isolated in a yield of 80% in the form of a translucent yellow oil. IR 1176 and 1386 cm xe2x88x921, xcexd (NSO2). NMR (CDCl3): 7.35, d, (1H); 7.25 d, (1H); 2.85, s, (6H); 1.0 s, (9H); 0.45, s, (6H).
12.5 ml (19.9 mmol) of a solution of n-butyllithium (1.6M solution in hexane) are added slowly to a solution of the compound obtained in Step B (4.67 g, 18 mmol) in 40 ml of anhydrous THF that has been brought to xe2x88x9278xc2x0 C., and then the whole is maintained at that temperature for 1 hour 30 minutes. A solution of p-cyanobenzaldehyde in 20 ml of THF, 3.3 g (25.1 mmol) is then added. The whole is stirred at xe2x88x9278xc2x0 C. for 0.5 hour, and then hydrolysed with an aqueous saturated NaHCO3 solution. When the reaction mixture is at room temperature, it is extracted with AcOEt and then washed with a saturated NaCl solution, dried over MgSO4 and concentrated to dryness.
After purification over silica gel (heptane/AcOEt 3/1), 5.8 g of the title product are obtained in a yield of 83%. IR: 3449 xcexd (OH); 2230 xcexd(CN); 1609 xcexd(Cxe2x95x90C); 1376 and 1146 xcexd cmxe2x88x921 (NSO2). NMR (CDCl3): 7.7, d, (2H); 7.6 d, (2H); 6.65 s (1H); 6.15 s (1H); 3.35 m (1H, OH); 2.85, s, (6H); 1.0 s, (9H); 0.45, s, (6H).
The compound obtained in Step C (4 g, 9.5 mmol) is brought to solution in 40 ml of THF. A mixture of AcOH/H2O (7:3) (40 ml) is then added, and the whole is stirred at room temperature for 2 hours. The reaction mixture is then hydrolysed in a mixture of ice and H2O, extracted with AcOEt and washed with a saturated NaHCO3 solution, and then with a saturated NaCl solution, dried over MgSO4 and concentrated to dryness. The residual solid is then triturated in heptane, and the title product is obtained in the form of white crystals, 2.57 g, in a yield of 89%. IR: 3200 2700 xcexd(OH); 2230 xcexd(CN); 1390 and 1152 xcexd cmxe2x88x921 (NSO2). NMR (CDCl3): 7.9, s, (1H); 7.75 and 7.55 2d, (4H); 6.55 s (1H); 6.15 d (1H); 3.25d(1H,OH); 3.0,s,(6H).
Elemental Microanalysis
4-(1H-Imidazol-5-ylcarbonyl)benzonitrile is obtained according to the method described by F. Effenberger; M. Roos; R. Ahmad; and A. Krebs; Chem. Ber.; 124 (7); 1639-1650; 1991, starting from the compound obtained in the preceding Step by oxidation with chromic anhydride in acetic acid at reflux.
The compound obtained in Step E of Preparation 15 is brought to solution in DMF, and 2 molar equivalents of Et3N and 1.1 molar equivalents of triphenylmethyl chloride are added in succession. The whole is stirred at room temperature for 96 hours. The reaction mixture is then hydrolysed in a mixture of H2O and ice, and extracted with AcOEt. After washing with a dilute 1N HCl solution and then with a saturated NaHCO3 solution and finally with a saturated NaCl solution, the reaction mixture is concentrated to dryness and purified over silica gel (heptane, AcOEt). 4-[(1-Trityl-1H-imidazol-5-yl)carbonyl]benzonitrile is obtained in the form of a crystalline compound in a yield of 78%.
This compound is obtained starting from the compound prepared in the preceding Step using the method described by I. M. Bell et al., J. Med. Chem.; .44; 2933-2949 2001, in 2 steps, replacing benzyl bromide by methyl iodide as alkylating agent.
A purification step over silica gel enables 4-[(1-methyl-1H-imidazol-5-yl)carbonyl]-benzonitrile to be isolated.
This compound is obtained according to the same process as for Preparation 15, in Step C using 4-(cyanophenyl)acetaldehyde as alkylating agent instead of p-cyanobenzaldehyde.
This compound is obtained according to the same process as for Preparation 16, using the compound obtained in Preparation 17.
This compound is obtained according to the same process as in Preparation 15, in Step C using 4-(chlorophenyl)benzaldehyde instead of p-cyanobenzaldehyde as alkylating agent.
This compound is obtained according to the same process as Preparation 16, using the compound obtained in Preparation 19.
This compound is obtained according to the same process as Preparation 15, in Step C using 4-(chlorophenyl)acetaldehyde instead of p-cyanobenzaldehyde as alkylating agent.
This compound is obtained according to the same process as Preparation 16, described above, using the compound obtained in Preparation 21.